Category: Ohio

COLUMBUS, Ohio – Seeking to improve on nature, scientists used a spice-based compound as a starting point and developed synthetic molecules that, in lab settings, are able to kill cancer cells and stop the cells from spreading.

The researchers are combining organic chemistry, computer-aided design and molecular biology techniques in developing and testing pharmaceutical compounds that can fight breast and prostate cancer cells. The synthetic molecules are derived from curcumin, a naturally occurring compound found in the spice turmeric.

Centuries of anecdotal evidence and recent scientific research suggest curcumin has multiple disease-fighting features, including anti-tumor properties. However, when eaten, curcumin is not absorbed well by the body. Instead, most ingested curcumin in food or supplement form remains in the gastrointestinal system and is eliminated before it is able to enter the bloodstream or tissues.

“Newer evidence describes how curcumin interacts with certain proteins to generate anti-cancer activity inside the body. We’re focusing on the pathways that are most involved in cancer and trying to optimize for those properties,” said James Fuchs, assistant professor of medicinal chemistry and pharmacognosy at Ohio State University and principal investigator on the project.

Fuchs presented the research today (8/17) at the American Chemical Society meeting in Philadelphia. He described a selection of the 40 compounds developed to date, emphasizing the synthetic molecules that appear to have the most potential to serve as the basis for anti-cancer drug development.

Fuchs and colleagues are continuing to refine compounds that are best structured to interact with a few overactive proteins that are associated with cell activity in breast and prostate cancers. Blocking these molecular targets can initiate cell death or stop cell migration in the cancers.

A major component of their strategy is called structure-based, computer-aided design, a relatively new technology in the drug discovery field. Before ever working with an actual compound, the scientists can make manipulations to computer-designed molecules and observe simulated interactions between molecules and proteins to predict which structural changes will make the most sense to pursue.

“Very small changes that may seem insignificant can have dramatic effects on these toxicity properties,” Fuchs said. “But most of the compounds we’ve made have been more potent than curcumin against the cancer cells.”

“Most of the interaction between our compound and the overactive protein comes from what are called hot spots on the protein’s surface,” said Chenglong Li, assistant professor of medicinal chemistry and pharmacognosy at Ohio State and an expert in computational chemistry. “For each spot, we can design small chemical fragments and link them together to make a molecule. This is what computer-aided design and modeling can do.”

Some of the most effective compounds have been tested for their effectiveness against human cancer cell lines – as well as whether they might be toxic to healthy cells. So far, the molecule favored by the researchers has a nearly 100-fold difference in toxicity to cancer cells vs. healthy cells, meaning it takes 100 times more of the compound to kill a healthy cell than it does to kill a cancer cell.

“Very small changes that may seem insignificant can have dramatic effects on these toxicity properties,” Fuchs said. “But most of the compounds we’ve made have been more potent than curcumin against the cancer cells.”

The computer-based predictions have suggested that the most effective compound developed to date can interact with proteins believed to be active in about 50 percent of all breast and prostate cancers.

“To be able to develop a drug that in the future could have potential to treat 50 percent of these cancers would be a major contribution,” said Jiayuh Lin, an investigator in Ohio State’s Comprehensive Cancer Center and an associate professor of pediatrics. Lin tests the experimental compounds in different types of breast and prostate cancer cell lines. He said some of the compounds also show potential to kill pancreatic cancer cells and inhibit cancer cell migration.

The computer-aided design also offers hints at the compounds’ suitability as the basis for a drug, such as whether the molecules will remain stable during metabolism and whether they will maintain a structure that the body can absorb into the bloodstream and tissues. The team is planning to continue refining the compounds before advancing to animal studies to test their effectiveness. The scientists hope to develop a chemotherapeutic agent available in pill form.

Additional members of the research group, dubbed the OSU Molecular Target Team, are Pui-Kai Li, chair and associate professor, and graduate students Jonathan Etter, Dalia Abdelhamid, Nicholas Regan, Deepak Bhasin, Bulbul Pandit and Katryna Cisek, all of Ohio State’s Division of Medicinal Chemistry and Pharmacognosy; and Ling Cen, Li Lin and Brian Hutzen of the Center for Childhood Cancer in the Research Institute at Nationwide Children’s Hospital in Columbus.

This work is supported by the Department of Defense Prostate Cancer Research Program, the James S. McDonnell Foundation, the National Foundation for Cancer Research, Ohio State’s Comprehensive Cancer Center and Ohio State’s College of Pharmacy.

COLUMBUS, Ohio – Researchers here have shown that in cell cultures, the stress hormone norepinephrine appears to promote the biochemical signals that stimulate certain tumor cells to grow and spread.

The finding, if verified, may suggest a way of slowing the progression and spread of some cancers enough so that conventional chemotherapeutic treatments would have a better chance to work. Eric Yang Ronald Glaser

The study also showed that stress hormones may play a completely different role in cancer development than researchers had once thought.

The results appear in the current issue of the journal Brain, Behavior and Immunity.

“We would not be surprised if we see similar effects of norepinephrine on tumor progression in several different forms of cancer,” explained Eric Yang, first author of the paper and a research scientist with the Institute for Behavioral Medicine Research (IBMR) at Ohio State University.

Yang and colleague Ron Glaser, a professor of molecular virology, immunology and medical genetics, last year showed that the stress hormone norepinephrine was able to increase the production of proteins in cultures of nasopharyngeal carcinoma tumor cells that can foster the aggressive spread of the disease, a process known as metastasis. Glaser is director of the IBMR and a member of the Comprehensive Cancer Center at Ohio State.

In this latest study, the researchers looked at a different type of cancer – multiple myeloma. One of several types of cancers of the blood, multiple myeloma strikes nearly 20,000 Americans each year, killing at least half that many annually. Patients diagnosed with this disease normally survive only three to four years with conventional treatments.

Yang and Glaser focused on three multiple myeloma tumor cell lines, each representing a different stage in the life of the disease, for their experiments. While all three tumor cell lines reacted to the presence of norepinephrine, only one, a cell line known as FLAM-76, responded strongly to the hormone. “The fact that this one cell line, of the three multiple myeloma cell lines studied, closely represents the early stages of the tumor, and that this is where we see the biggest effect, is what makes this work more clinically relevant.”

The norepinephrine binds to receptors on the surface of the cells, sending a signal to the nucleus to produce a compound known as VEGF — vascular endothelial growth factor – that is key to the formation of new blood vessels, which the tumor must have to grow.

The FLAM-76 cell line was prepared from multiple myeloma tumor cells taken from a patient whose disease had not yet progressed too far from its original site in the bone marrow where blood cells are formed.

“It turns out that FLAM-76 tumor cells more closely represent the earlier stages of the disease when blood vessel formation, a process called angiogenesis, is needed for disease progression,” Yang said.

“The fact that this one cell line, of the three multiple myeloma cell lines studied, closely represents the early stages of the tumor, and that this is where we see the biggest effect, is what makes this work more clinically relevant,” Glaser said.

The researchers believe that blocking these receptors would slow the process of the growth of more blood vessel to the tumor, delaying disease progression and perhaps allowing treatments to be more effective. Widely used “beta-blocker” drugs now prescribed for high blood pressure work by blocking these same particular cell surface receptors, Yang said.

“This approach wouldn’t kill the tumor cells but it would diminish the blood supply to the tumor cells and slow them down, and that could translate into a longer and better quality of life for the patient,” Glaser said.

The researchers and their colleagues are now working with other forms of cancer to test the effects of stress hormones like norepinephrine on their growth.

Glaser added that these kinds of results may change the way scientists are looking at a link between stress and the development and spread of cancer. In the past, he said, the focus was on how stress hormones weakened the immune system, allowing certain tumors to evade the body’s defenses.

“Now we have these stress hormones, not only affecting the immune response, but also acting directly on the tumor cells and inducing changes in the molecules made by those same tumor cells,” Glaser said.

“This has important implications for the spread of the tumor and metastasis.”

Elise Donovan, a researcher with the IBMR, and Don Benson, a researcher with Ohio State’s Comprehensive Cancer Center, also worked on the project. The research was funded in part by the National Cancer Institute.